Suppressed expression of insulin‐like growth factor binding protein‐1 mRNA in the endometrium: A molecular mechanism associating endometrial cancer with its risk factors

Abstract

The insulin-like growth factor (IGF) system is thought to function as a mediator of steroid hormone actions in the endometrium. IGFs (IGF-I and IGF-II) are also potent mitogens in endometrial cancer. The biological actions of IGFs are modulated by specific binding proteins (IGFBP)--6 cloned and sequenced so far--which may either inhibit or enhance the effects of IGF at the cellular level. In the endometrium, IGFBP-1 gene expression is stimulated by progesterone and inhibited by insulin, while IGFBP-1 inhibits the mitogenic action of IGF-I. In this study, we used a quantitative reverse transcriptase polymerase chain reaction (RT-PCR) to investigate IGFBP-1, IGFBP-2, IGFBP-4, IGFBP-5 and IGFBP-6 gene expression in endometrial cancer tissues. Endometrial cancer tissue samples were collected from 20 women (aged 54-79 yrs) with stage I to II well-differentiated endometrial adenocarcinoma. Samples of normal endometrium (n = 14) obtained from women undergoing tubal ligation in various phases of the menstrual cycle, and normal early-pregnancy endometrium (decidua) were studied for comparison. In endometrial cancer tissues, the IGFBP-1 mRNA was undetectable or minimally expressed when studied by RT-PCR. The mean (+ SD) levels of IGFBP-2 and IGFBP-4 and IGFBP-5 mRNAs in endometrial cancer tissues did not differ from those in normal endometrium, in which no cyclic variation was observed, suggesting that the genes encoding IGFBP-2, IGFBP-4 and IGFBP-5 are not hormonally regulated in the endometrium. The IGFBP-6 mRNA expression showed a significant cyclic variation in normal endometrium, with low levels in late-proliferative and early- to mid-secretory phases and high expression in late-secretory and early-proliferative phases. In endometrial cancer tissues, the mean IGFBP-6 mRNA level was similar to that in cycling endometrium during the peri-ovulatory period. In summary, a continuous stimulation of the endometrial epithelial cells by IGFs with suppressed IGFBP-1 expression may lead to an imbalance in the IGF system of the endometrium and trigger an uncontrolled cell proliferation, ultimately resulting in malignant transformation.

Energy balance and cancer: the role of insulin and insulin-like growth factor-I

“…In addition to these studies, one large case-control study showed an increase in endometrial cancer risk in postmenopausal women (Troisi et al 1997) with elevated serum levels of C-peptide. A similar but much smaller study also showed higher fasting insulin levels in thirty-two postmenopausal patients with endometrial cancer compared with eighteen controls (Rutanen et al 1994).…”

Evaluating vaspin and adiponectin in postmenopausal women with endometrial cancer

“…Progesterone, on the other hand, is widely accepted as a protective factor against endometrial carcinogenesis due to its antiproliferative effects on endometrial tissue by promoting a local increase in IGF binding protein 1 (IGFBP) synthesis. Insulin manifests its carcinogenic characteristics by increasing the bioactivity of IGF1 while also downregulating the synthesis of IGFBP1 in endometrial tissue (Murphy & Ghahary 1990, Rutanen et al 1994. Furthermore, chronic hyperinsulinemia may lead to ovarian hyperandrogenism, and increased peripheral aromatization of androgens to estrogen may increase the risk of endometrial cancer, particularly in postmenopausal women (Kaaks et al 2002).…”

Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling

“…Among them seven genes have been reported previously as differentially expressed in endometrial tumors. Lactotransferrin (LTF) was upregulated (Walmer et al, 1995), whereas six genes including SFRP4, DCN, IGFBP6, HGF, WT1 and WNT4 were downregulated in the endometrial tumors (Rutanen et al, 1994;Bui et al, 1997;Yoshida et al, 2002;Muller-Tidow et al, 2003;Smid-Koopman et al, 2004;Acs et al, 2004;Hrzenjak et al, 2004). Of these genes, only WT1 was been specifically associated with endometrioid cancer (Acs et al, 2004).…”